Acute leukemia with KMT2A rearrangement: A master of disguise.

Mixed-phenotype acute leukemia (MPAL) is a rare form of leukemia with ambiguous lineage, and there are challenges in accurately diagnosing this entity according to formal criteria. Here we report a case which was initially diagnosed as "AML" based on atypical peripheral blood flow cytometry that was subsequently determined to be B-ALL with KMT2A rearrangement based on marrow results. Although KMT2A rearrangements represent a defining genetic abnormality for acute leukemia of ambiguous lineage, this case did not meet the criteria for MPAL based on WHO 2022 criteria. This case highlights the diagnostic challenges of MPAL and the potential limitations of the current classification. We discuss the most appropriate workup and management of these patients and identify areas for future study.

TP53 or Not TP53: That Is the Question.

Azacitidine and venetoclax are a standard first-line regimen for patients with newly diagnosed unfit acute myeloid leukemia (AML). In a pooled subset analysis, TP53-mutated AML with poor-risk cytogenetics does not appear to benefit from the addition of venetoclax to azacitidine. This has clinical implications as these patients should be preferentially treated with alternative regimens. See related article by Pollyea et al., p. 5272.

Engineering Tools for Regulating Hypoxia in Tumour Models.

Major advances in the field of genomic technologies have led to an improvement in cancer diagnosis, classification and prognostication. However, many cancers remain incurable due to the development of drug resistance, minimal residual disease (MRD) and disease relapse, highlighting an incomplete understanding of the mechanisms underlying these processes. In recent years, the impact of non-genetic factors on neoplastic transformations has increasingly been acknowledged, and growing evidence suggests that low oxygen (O2 ) levels (ie hypoxia) in the tumour microenvironment play a critical role in the development and treatment of cancer. As a result, there is a growing need to develop research tools capable of reproducing physiologically relevant O2 conditions encountered by cancer cells in their natural environments in order to gain in-depth insight into tumour cell metabolism and function. In this review, the authors highlight the importance of hypoxia in the pathogenesis of malignant diseases and provide an overview of novel engineering tools that have the potential to further drive this evolving, yet technically challenging, field of cancer research.

CD123-targeted therapy in acute myeloid leukemia.

INTRODUCTION: Acute myeloid leukemia (AML) results from the neoplastic transformation of a hematopoietic stem cell. While therapeutic progress has stagnated for several decades, recent progress in the genomic classification of AML has paved the way for multiple new drug approvals. These long-awaited achievements represent a paradigm shift in the approach to a disease that has largely been managed with conventional chemotherapy since the 1970s. With the evolution of targeted AML therapies, novel agents continue to be developed with the goal to improve efficacy while minimizing toxicity. Monoclonal antibodies targeting AML-specific surface markers have emerged as promising candidates to improve outcomes. CD123, interleukin-3 receptor alpha chain [IL-3 Rα], is highly expressed in AML, particularly within the AML stem cell compartment. Several CD123-targeted strategies are currently being evaluated in clinical trials. AREAS COVERED: The authors herein discuss recent clinical data in CD123-directed therapy in AML. A computerized PubMed search was conducted using key words relevant to the various sections of this article. Relevant abstracts presented at the American Society of Hematology, the European Hematology Association, and the American Society of Clinical Oncology were also reviewed. EXPERT OPINION: CD123 represents a suitable therapeutic target that has the potential to improve AML patient outcomes.

Clinical conundrum: managing iron overload after renal transplantation.

Iatrogenic iron overload, which is not uncommon in patients undergoing long-term haemodialysis, arises from a combination of multiple red cell transfusions and parenteral iron infusions that are administered to maintain a haemoglobin concentration of approximately 10 g/dL. Although iron overload due to genetic haemochromatosis is conventionally managed by phlebotomy, patients with haemoglobinopathies and chronic transfusion-induced iron overload are treated with iron-chelation therapy. However, the management of iron overload in our patient who presented with hepatic dysfunction and immunosuppressive drug-induced mild anaemia in the post-renal transplant setting posed unique challenges. We report on the decision-making process used in such a case that led to a successful clinical resolution of hepatic iron overload through the combined use of phlebotomy and erythropoiesis stimulating agents, while avoiding use of iron-chelating agents that could potentially compromise both hepatic and renal function.

Secondary AML Emerging After Therapy with Hypomethylating Agents: Outcomes, Prognostic Factors, and Treatment Options.

PURPOSE OF REVIEW: Secondary AML (s-AML) encompasses a distinct subgroup of AML with either therapy-related AML or AML arising from preexisting myeloid neoplasms. Despite recent advances in the treatment armamentarium of AML, outcomes remain poor in s-AML. The purpose of this review is to highlight distinct characteristics, prognostic factors, and treatment options for patients with s-AML. Further, we focus on a distinctly poor-risk subgroup of s-AML with previous exposure to hypomethylating agents (HMAs) and describe ongoing clinical trials in this patient population. RECENT FINDINGS: CPX-351 (liposomal daunorubicin and cytarabine) is the first drug approved for s-AML and represents an advancement in the management of fit patients with this subtype of AML. Despite incremental improvement in remission rates and survival, long-term survival remains poor. Patients who have received prior HMAs for antecedent MDS rarely benefit from CPX-351 or other cytotoxic chemotherapy regimens. The approval of venetoclax in combination with azacitidine has led to a paradigm shift in the management of newly diagnosed older unfit AML patients; however, patients with s-AML and prior HMA therapy were excluded from the landmark randomized phase 3 study. Several early phase clinical trials with both low- and high-intensity therapies are ongoing for s-AML patients, though prior HMA exposure limits inclusion in many of these studies that include HMAs. Patients with s-AML previously treated with an HMA have dismal outcomes with standard therapeutic options and are under-represented in clinical trials. Trials investigating novel therapeutic options in this population are critically needed.

Management of fever and neutropenia in the adult patient with acute myeloid leukemia.

INTRODUCTION: Febrile neutropenia represents one of the most common treatment-associated complications in the management of acute myeloid leukemia (AML) and is considered an oncologic emergency. Rapid and detailed workup as well as the initiation of empiric broad-spectrum antibiotic therapy are critical to avoid sepsis and to reduce mortality. Although a definitive source of infection is frequently not identified, the severely immunosuppressed status of the AML patient undergoing cytotoxic therapy results in a high risk for a wide array of bacterial, fungal, and viral etiologies. AREAS COVERED: The authors herein review the diagnostic and therapeutic approach to the neutropenic leukemia patient based on the current knowledge. Special consideration is given to the rapidly changing therapeutic landscape in AML, creating new challenges in the management of infectious complications. EXPERT OPINION: Multidrug-resistant organisms pose a major challenge in the management of neutropenic fever patients with hematologic malignancies - including AML. Future directions to improve outcomes demand innovative treatment approaches as well as advances in biomarker research to facilitate diagnosis and disease monitoring. Recent achievements in AML-targeted therapy led to an increased incidence of differentiation syndrome, a potentially life-threatening side effect that frequently resembles clinical infection and requires prompt recognition and aggressive intervention.

Treatment of Acute Myeloid Leukemia in the Era of Genomics-Achievements and Persisting Challenges.

Acute myeloid leukemia (AML) represents a malignant disorder of the hematopoietic system that is mainly characterized by rapid proliferation, dysregulated apoptosis, and impaired differentiation of leukemic blasts. For several decades, the diagnostic approach in AML was largely based on histologic characteristics with little impact on the treatment decision-making process. This perspective has drastically changed within the past years due to the advent of novel molecular technologies, such as whole genome next-generation sequencing (NGS), and the resulting knowledge gain in AML biology and pathogenesis. After more than four decades of intensive chemotherapy as a "one-size-fits-all" concept, several targeted agents have recently been approved for the treatment of AML, either as single agents or as part of combined treatment regimens. Several other compounds, directed against regulators of apoptotic, epigenetic, or microenvironmental pathways, as well as modulators of the immune system, are currently in development and being investigated in clinical trials. The constant progress in AML research has started to produce improved survival rates and fueled hopes that a once rapidly fatal disease can be transformed into a chronic condition. In this review, the authors provide a summary of recent advances in the development of targeted AML therapies and discuss persistent challenges.